This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Dengue is a pantropical mosquito-borne flavivirus infecting 50 to 100 million people a year. A group of four closely related serotypes, DENV1-DENV4, they cause a wide spectrum of disease, from relatively mild dengue fever (DF) to the more severe dengue hemorrhagic fever (DHF) and shock syndrome (DSS). Recent decades have seen an increase in dengue activity throughout its range, marked by more frequent and severe epidemics. Although the causes of this re-emergence are probably multifold, from vector expansions to hyper-endemicity leading to antibody-dependent enhancement (ADE), the importance of virus strain variation in virulence has been implicated in other studies and supported by our preliminary findings. We pair a longitudinal evolutionary study of dengue viruses co-circulating in the Caribbean and demonstrating dramatic outbreak dynamics over two decades, with experimental infections by outbreak strains of cellular models and mosquitoes, to identify the genetic determinants and phenotypic correlates of epidemic potential and disease emergence. Our findings will provide a better understanding of the evolutionary drivers of disease emergence along with a set of informative models for characterizing emergent strains.